Journal Club: Intensive Glucose Management in Type 1 Diabetes Mellitus Preserves Glomerular Filtration Rate

Editor – Diabetes is the cause of approximately 40% of kidney failure in the United States. Preventing nephropathy and its subsequent progression represents "the holy grail" of nephrology. Dr. Tejas Patel is a regular contributor. He is an attending nephrologist at Caritas-St. Elizabeth’s Medical Center and Tufts University School of Medicine, to review an important paper for Journal Club. In addition to his clinical responsibilities, Tejas is Assistant Program Director for Internal Medicine and a Medical Director. Tejas’s research interest is in anemia and the epidemiology of kidney disease and it’s complications.

The incidence of Type 1 Diabetes Mellitus (T1DM) is on the rise with an increase of up to 5% in certain parts of the world.  

The multinational multicenter NIH-funded Diabetes Control and Complications Trial (DCCT), published in NEJM, has fundamentally changed the way we treat T1DM [1].  1441 persons with T1DM with either no or microalbuminuria were randomly assigned to either intensive glycemic reduction (hemoglobin A1C target 6.0%) or to conventional treatment aimed at preventing hyperglycemic symptoms.  The inclusion criteria were serum creatinine <1.2mg/dL or in a subset iothalamate creatinine clearance of >100ml/min/1.732m2.  After mean follow up of 6.5 years, the mean hemoglobin A1C achieved was 7.2 + 0.9% versus 9.1+1.3% in intensive arm and conventional arm respectively.  There was reduction in microalbuminuria (>40mg/g) by 39% and albuminuria (>300mg/g) by 54% in the intensive arm compared to conventional arm.  

In a follow-up study to DCCT, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.  The findings of the observational cohort on the effect of intensive glycemic control on glomerular filtration rate and renal outcomes were recently published in NEJM. Figure 1 depicts the schemes of both the DCCT and EDIC studies.

In the EDIC study, impaired GFR was defined as GFR less than 60 ml/min/1.732m2 at two consecutive study visits, usually 1 year apart.  The baseline characteristics of age, gender, duration of diabetes, incidence of hypertension were similar.  In addition, no one was on RAAS blocker initially and the use of RAAS blocker was strongly discouraged throughout the study.   The findings of the study are outlined in Tables 1 and 2.  

• Over a median follow-up of 22 years in the combined studies:
• impaired GFR developed in 24 people in intensive arm and 46 in the conventional therapy (risk reduction with intensive therapy 50%, P=0.006).  
• End stage renal disease (ESRD) developed in 8 people in intensive arm and 16 in the conventional therapy arm. 
• The mean eGFR was higher by 2.5ml/min/1.732m2 in intensive arm compared to control.  

The authors concluded that there was a significantly lower incidence of impaired GFR in the intensive treatment arm compared to the conventional arm.   This study and follow-up at 8 years confirm the long term renal benefits of tight glucose control in T1DM patients [3].

I would like to emphasize the following potential limitations:

• Though the use of RAAS blockers was discouraged, by the end of the EDIC study at year 16, 57% of participants in the conventional arm and 53% in the intensive arm were on one of the RAAS blockers.  The authors do not report whether the use was statistically significant but reports that adjusting for the use of RAAS blocker did not change the risk. Further, duration of RAAS inhibitors in each group would have been helpful.
• The causes of deaths were not disclosed.  If the majority of causes were due to a vascular event, the clinical significance would be more appealing.
• “Tight” glucose control was at a hemoglobin A1C of 8.0% (see Table 1), which is suboptimal compared to the American Diabetes Association target hemoglobin A1C of 7% or less.
• Incidence of hypoglycemia in either group was not disclosed.  We do know that the first six years of DCCT study had significant hypoglycemic events requiring modification of protocol.
• It is not clear from this study how much of the reduction in GFR was related to glycemic control.  It would be interesting to know if there was any difference in ‘glycemic variability’ or fluctuations or even post-prandial excursions of glucose between the groups.
• What is the mechanism of sustained benefit of initial tight glucose control?  The concept of ‘metabolic memory’ has been quoted quite widely but the exact mechanism remains to be determined.  Continued development of diabetic complications even after achieving adequate glucose control suggests ‘metabolic memory’ of previous high glucose exposure.  So, even after improving the glucose homeostasis, the risk for complications does not return to baseline.  Alternatively, early control of glucose leads to lasting benefits[4].  Several experiments suggest that an epigenetic mechanism might be involved in this phenomenon[5]. 

Diabetes research has heavily focused on genetic aspects of disease predisposition and complications.  However, it is increasingly being recognized that there is a more complex interaction between genes and the environment.  Epigenetics is the study of heritable patterns of gene expression and subsequent phenotypic changes that occur without alterations in the underlying DNA sequences.  Chromatin is the combination of DNA and histone proteins that make up the nucleus.  Changes in chromatin have been linked to gene transcription through various pathways (DNA methylation and post transcriptional modification).  In vitro and animal studies have shown upregulation of genes promoting fibrosis and inflammation after modifying histones.  It is thought that these changes are persistent even after glucose levels are normalized, thus making it plausible that histone modification by various enzymes probably plays role in sustained injury to the target organs. Figure 2 depicts the concept of epigenetics and its role in human diseases.  

Figure 3 is a cartoon of potential pathways that lead to renal damage in high glucose state.  Details of the mechanisms have been well described in reference 5.

In summary, this study helps strengthen the concept of ‘metabolic memory’ and it remains to be seen if we can modify certain epigenetic factors which may expand our therapeutic armamentarium.  Until then, tight glucose control remains the main stay to help prevent renal complications.  A similar finding was reported in T2DM people enrolled in United Kingdom Prospective Diabetes (UKPDS) trial [6].

References

1.   The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med, 1993. 329(14): p. 977-86

2.   Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes. N Engl J Med. epubished Nov 12, 2011

3.   Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA, 2003. 290(16): p. 2159-67.

4.   Ceriello, A., M.A. Ihnat, and J.E. Thorpe, Clinical review 2: The "metabolic memory": is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab, 2009. 94(2): p. 410-5.

5.   Villeneuve, L.M., M.A. Reddy, and R. Natarajan, Epigenetics: deciphering its role in diabetes and its chronic complications. Clin Exp Pharmacol Physiol. 38(7): p. 401-9.

6.   Holman, R.R., et al., 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med, 2008. 359(15): p. 1577-89.